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Structural insights into the inhibition mechanism of human sterol O-acyltransferase 1 by a competitive inhibitor
- Source :
- Nature Communications, Nature Communications, Vol 11, Iss 1, Pp 1-11 (2020)
- Publication Year :
- 2020
-
Abstract
- Sterol O-acyltransferase 1 (SOAT1) is an endoplasmic reticulum (ER) resident, multi-transmembrane enzyme that belongs to the membrane-bound O-acyltransferase (MBOAT) family. It catalyzes the esterification of cholesterol to generate cholesteryl esters for cholesterol storage. SOAT1 is a target to treat several human diseases. However, its structure and mechanism remain elusive since its discovery. Here, we report the structure of human SOAT1 (hSOAT1) determined by cryo-EM. hSOAT1 is a tetramer consisted of a dimer of dimer. The structure of hSOAT1 dimer at 3.5 Å resolution reveals that a small molecule inhibitor CI-976 binds inside the catalytic chamber and blocks the accessibility of the active site residues H460, N421 and W420. Our results pave the way for future mechanistic study and rational drug design targeting hSOAT1 and other mammalian MBOAT family members.<br />Sterol O-acyltransferase 1 (SOAT1, also named ACAT1) is an endoplasmic reticulum resident enzyme which catalyzes the esterification of cholesterol to generate cholesteryl esters. Here, authors report cryo-EM structures of human SOAT1 which reveal the binding site of the competitive inhibitor CI-976.
- Subjects :
- 0301 basic medicine
Science
Sterol O-acyltransferase
General Physics and Astronomy
Drug design
MBOAT
Ligands
General Biochemistry, Genetics and Molecular Biology
Article
Substrate Specificity
03 medical and health sciences
Structure-Activity Relationship
Transferases
Cryoelectron microscopy
Humans
Enzyme Inhibitors
lcsh:Science
SOAT1
Multidisciplinary
Binding Sites
030102 biochemistry & molecular biology
biology
Chemistry
Endoplasmic reticulum
Active site
Endocrine system and metabolic diseases
General Chemistry
Sterol
030104 developmental biology
HEK293 Cells
Cardiovascular diseases
Biochemistry
biology.protein
Biocatalysis
lcsh:Q
lipids (amino acids, peptides, and proteins)
Protein Multimerization
Cholesterol storage
Sterol O-Acyltransferase
Subjects
Details
- ISSN :
- 20411723
- Volume :
- 11
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Nature communications
- Accession number :
- edsair.doi.dedup.....b57a3e7a544beab6426e75a5fbff0052